Ratting Out Disease
A research project at Rice has brought scientists to the brink of comprehending a long-standing medical mystery that may link cardiovascular disease, osteoporosis and perhaps even Alzheimer’s disease. And for that, we can thank the rat.
Rice evolutionary biologist Michael Kohn and his collaborators — Roger Price of Baylor College of Medicine and Hans-Joachim Pelz of the Julius Kuehn Institute in Germany — report they have found that common rats with a genetic mutation have developed a resistance to rat poison, aka warfarin. That’s good news for the rats, but it comes at a price. The mutation also leaves them susceptible to arterial calcification and, potentially, osteoporosis, and that’s good news for humans.
In the mutated gene, the researchers found what could be the link that solves the calcification paradox: the puzzling association between metabolic bone disease and vascular calcification that has eluded researchers for years. Kohn said a good part of the answer lies in the vitamin K cycle, which is known to regulate the coagulation of blood — clotting. It also is suspected of helping keep calcium out of the body’s vessels and in its bones, which has particular ramifications for postmenopausal women for whom loss of bone density is a serious issue.
Warfarin has long served humans as a medicine called Coumadin, because it interferes with the vitamin K cycle. In regulated doses, it thins the blood by reducing its ability to coagulate, which helps prevent heart attacks, stroke and blood clots. In larger doses, it once excelled as rat poison; rats that ingested the poison would simply bleed to death. But the genetic mutation in rats effectively blocks that interference.
“I have a feeling the mutation predated the introduction of warfarin,” said Kohn. “But it was rare because it causes side effects. It’s not an advantageous mutation unless it’s exposed to warfarin.”
Rats without the mutation died, while those with the mutation multiplied. “These rats, in the absence of poison, suffer from cardiovascular disease, just like we do,” said Kohn, who added that the kidneys of rats in the study were “calcified to an extent that is shocking.”
His hope is that the equivalent gene in humans turns out to be the key to a number of ills.
“As you look at humans, this calcification of arteries is, I suspect, a very important precondition to thrombosis and stroke,” he said. “So to find such a strong effect astonished us. We had a tough time publishing the paper because people might have thought it was too good to be true, that you can explain the effect to such a degree by looking at just one gene.”
Kohn and his colleagues have begun a study on osteoporosis in rats that have the mutation, and early results are promising. “The prediction is the mutant rats have a lower bone density,” he said. “I think if we complete and confirm that as well, it would be a major breakthrough. That means one gene — one mutation — explains the so-called calcification paradox.”
Finally, he noted, Alzheimer’s patients tend to be vitamin K-deficient, which opens up avenues for further study. “Could there be one mutation that explains osteoporosis, arteriosclerosis and Alzheimer’s?” he wondered. “That would be huge.”